Ation and their therapeutic application novel derivatives of 1-cinnamyl benzimidazole their process of prepar

ABSTRACT

A COMPOUND OF THE FORMULA IS DIALKYLAMINO IN WHICH THE TWO ALKYLS ARE IDENTICAL, OR PIPERIDINO, MORPHOLINO OR PYRROLIDINO IS PREPARED BY REACTING THE CORRESPONDING 2-SUBSTITUTED BENZIMIDAZOLE WITH CINNAMYL CHLORIDE. THE COMPOUNDS POSSESS HYPOTENSIVE, VASODILATRIC, RESPIRATORY ANALEPTIC, ANALGESIC, ANTIINFLAMMATORY, SPASMOLYTIC AND DIURETIC PROPERTIES.   -N&lt;(-)   IN WHICH   -CH2-N&lt;(-)   WHEREIN R IS ALKYL OR HYDROXYALKYL HAVING 1 TO 3 CARBON ATOMS, OR PHENYL SUBSTITUTED WITH AT LEAST ONE ALKOXY OR AT LEAST ONE HALOGEN, OR BENZYL DISUBSTITUTED ON THE BENZENE RING WITH HALOGEN AND ALKOXY, OR   1-(C6H5-CH=CH-CH2-),2-R-BENZIMIDAZOLE

United States Patent 3,758,459 NOVEL DERIVATIVES 0F l-CINNAMYL BENZIM- IDAZOLE, THEIR PROCESS OF PREPARATION AND THEIR THERAPEUTIC APPLICATION Claude P. Fauran, Paris, Jeannine A. Eberle, Chatou, Guy M. Raynaud, Paris, and Yves J. Bailly, Nanterre, France, assignors to Delalande S.A., Courbevoie (Hautsde-Seine), France No Drawing. Filed Nov. 26, 1971, Ser. No. 202,596 Claims priority, applicatitarslgrance, Nov. 27, 1970,

Int. Cl. C0711 49/38 US. Cl. 260-240 K 9 Claims ABSTRACT OF THE DISCLOSURE A compound of the formula wherein R is alkyl or hydroxyalkyl having 1 to 3 carbon atoms, or phenyl substituted with at least one alkoxy or at least one halogen, or benzyl disubstituted on the benzene ring with halogen and alkoxy, or

in which is dialkylamino in which the two alkyls are identical, or piperidino, morpholino or pyrrolidino is prepared by reacting the corresponding 2-substituted benzimidazole with cinnamyl chloride. The compounds possess hypotensive, vasodilatric, respiratory analeptic, analgesic, antiinflammatory, spasmolytie and diuretic properties.

The present invention relates to novel derivatives of l-cinnamyl benzimidazole, their process of preparation and their therapeutic application.

The novel derivatives according to the present invention correspond to the general formula:

in which R represents:

an alkyl radical having 1 to 3 carbon atoms, optionally substituted by a hydroxy radical;

a phenyl ring substituted by at least one alkoxy radical or at least one halogen atom;

a benzyl radical, disubstituted in the benzene ring by a halogen atom and an alkoxy group; or

a radical of the formula:

3,758,459 Patented Sept. 11, 1973 ice cordance with the invention comprises reacting a 2-substituted benzimidazole of the general formula:

R \N/J. (II) with cinnamyl chloride of the formula:

o1-oH,-on=oH- in the presence of sodium hydride (NaH) in dimethylformamide as solvent, R having the same signification as in Formula I above.

The following preparations are given by way of example in order to illustrate the invention.

EXAMPLE 1 l-cinnarnyl 2-methyl benzimidazole (Code No. 69126) 0.1 mol of sodium hydride (in the form of a 50% suspension in a mineral oil) is added, over a period of 20 minutes, to a solution of 0.1 mol of 2-methyl benzimidazole in ml. of dimethylformamide.

The temperature increases to 40 C. The mixture is warmed and maintained at 50 C. for 10 minutes with agitation. The reaction mixture is allowed to cool to ambient temperature and then, over a period of 10 minutes, a solution of 0.1 mol of cinnamyl chloride in 20 ml. of dimethylformarnide is added thereto. The temperature increases to 40 C. The mixture is a violet-like colour. The mixture is then heated for 20 minutes at 80 C., diluted with 200 ml. of water, extracted with chloroform and the extract is washed with water, dried and evaporated. The product is recrystallised from ethyl acetate and dried over P 0 Melting point=102 C. Yield=50% Empirical formula=C H N Elementary analysis.-Calcd. (percent): C, 82.22; H, 6.50; N, 11.28. Found (percent): C, 82.22; H, 6.72; N, 11.39.

EXAMPLE 2 l-cinnamyl 2-(3'-hydroxypropyl) benzimidazole and its hydrochloride (Code No. 69282) 0.5 mol of sodium hydride is added, at ambient temperature and over a period of 15 minutes, to a solution of 0.5 mol of 2-(3-hydroxypropyl) benzimidazole in 400 ml. of dimethylformamide whilst ensuring that the temperature does not exceed 40 C. The reaction mixture is there- 'after maintained at 50 C. for 10 minutes. The mixture is then allowed to cool to 30 C. and then cinnamyl chloride is added thereto over a period of 10 minutes. The reaction mixture is maintained at 80 C. for 20 minutes is then allowed to cool to ambient temperature. The mixture is diluted with water and the oil so formed is extracted with chloroform. The mixture is then dried and evaporated and the residue formed is crystallised by the addition of ether. 67 g. of l-cinnamyl 2-(3'-hydroxypropyl) benzimidazole are obtained by recrystallisation from an ethanol/petrol ether (33%) mixture.

The compounds of Formula I have been tested on animals in the laboratory and have been shown to possess hypotensive, vasodilatric, respiratory analepitc, analgesic, antiinflammatory, spasmolytic and diuretic properties.

( 1) Hypotensive properties: The compounds of the Melting p i 95o 5 Formula I, when administered by intravenous or intro- Yie1d:46% duodenal means to an anesthetised rat, provoke a re- Empirical fOrmu1a:C19H20NO2 ductlon 1n the arterial pressure.

By way of example, the results obtained with two com- Elemenfary analysls.calcd- (P U H, pounds of the Formula I are given in the following 6.90 N, 9.58. Found (percent): C, 78.21; 'H, 7.15; N, Table 11;

The hydrochloride may be obtained by treating a solu- TABLE II tion of 0.2 mol of the compound described above in 500 agff i g ml. of ethanol with 20 ml. of 10 N hydrochloric alcohol. 15

The residue is evaporated and recrystallised from ISO- gggg g Dose propyl alcohol. tested administered percent min.

Melting point=145 C. 69126 50 40 Yie1d=82% 7064 2mg./kg./i.v Empirical formula=C H ClNO (2) Vasodilatric properties: The compounds of Elementary analysis.Calcd. (percent): C, 69.39; H, Formula I are capable of augmenting the flow in coronary 6.44; N, 8.52. Found (percent): C, 69.44; H, 6.41; N, canals in the isolated heart of a guinea-pig when they are 8.36. 25 added to perfusion liquids for this organ.

The compounds listed in the following Table I have By way of example, the results obtained with two of been prepared according to the methods disclosed in the compounds of Formula I are given in the following the Examples 1 and 2: Table III:

TABLE I Elementary analysis Melting Yield Calculated Found Empirical Molecular point; per- Oode No. R Form formula. weight 0.) cent 0 H N O H N 69125 CH(OH)CHz Base CrsHrsNzO 278. 34 144 43 77. 67 6. 52 10. 07 77. 46 6. 34 10. 11 69244 CHzOH ...do. CnHmNzO 264. 31 162 57 77.24 6. 10 10. 60 77. 10 5. 92 10. 54

69338 ?CH3 Maleate. CzoH aNzO 516.53 160 78 67.43 5.46 5.62 67.24 5.42 5.53

-- OCH;

Base....- C2zH C1N2 344. 83 100 20 76.62 4.97 8. 12 76. 62 4.99 8. 10

69330 (31 '.-.-d0..--.. CzaHzzClNzO 402. 91 110 31. 5 74. 52 5.75 6.95 74.47 5.99 6.

CHz

OCzHs 70123...'.:'..; ('31 '.'-.d0...... C24H2iClNzO 388. 88 199 43 74.12 5. 44 7.20 74. 14 5. 35 7.21

-o1120 CH3 7027 --CHzN(nC H1)z HCl CzqHaoClNa 383. 126 22 71.94 7.88 10.05 71.83 7.85 10.82

7023 CH N/ H01 Ca2 2eC1Na 367. 91 191 40 71.82 6.52 11.42 72.02 7.14 11.54

7040 CH N/ HCl C21H24C1N30 369.88 183 51 68.19 6. 54 11.36 67.99 6. 53 11.42

7064 HCl C21H24C1N3 353.88 216 20 71.27 6.84 11.88 71.46 6.92 11.67

TABLE III Augmenta- Dose introtion of flow dueed into in isolated Code No. of comthe erfuheart, pound tested sion quor percent 2.5 gJml. 70 2.5 g./ml- 50 (3) Respiratory analeptic properties: The compounds of Formula I, administered by intravenous means to an anesthetised guinea-pig, are capable of opposing the respiratory depression provoked by morphine.

By way of example, the results obtained with three of the compounds of Formula I are given in the following Table IV:

(4) Analagesic properties: The compounds of Formula I, administered by oral means to the mouse, are capable of reducing the number of painful stretchings produced by the intraperitoneal injection of acetic acid.

By way of example, the results obtained with several of the compounds of Formula I are given in the following Table V:

TABLE V Diminution of number of painful stretch- Code No. of Dose adminings, compound tested istered percent 7027 100 mg./kg./p.o-- 45 100 mg. /kg./p.0 45 100 mg.Ikg./p 45 100 mgJkgJp. 70 100 mg./kg./p.o- 65 (5) Antiinflammatory properties: The cmopounds of Formula 1, administered by oral means, to the rat, are capable of reducing the under-planatary oedema provoked by the local injection of carraghenine.

By way of example, the results obtained with two of the compounds or Formula I are given in the following (6) Spasmolytic properties: The compounds of Formula I, introduced in the conserving medium, are capable of opposing the contractural action of barium chloride on the isolated duodenum of the rat. This activity is appreciable taking papaverine as standard.

By way of example, the spasmolytic activity of compound Nos. 69282, 7023 and 7064 is equivalent to that of papaverine.

(7) Diuretic properties: The compounds of Formula I, administered by oral means to the rat and mouse, simultaneously with a volume of 1 ml. of an isotonic solution of sodium per 25 g. of the corporeal weight 'of the mouse and with 2.5 ml. per 100 g. of the corporeal weight of the rat, are capable of provoking an augmentation of the volume of urine emitted by reference to control animals, the volume being measured for 4 hours following administration.

By way of example, the results obtained with several of the compounds of Formula I are given in the following Table VII:

TABLE VII Augmentation of urinary elimina- Code No. of com- Dose admintlon, pound tested lstered percent 7078--. 10 mg.lkg.lp.o--.. 60 69125.. 10 mg./kg./p.o 69282.. 10 mg./kg./p.o 45 69338 10 mg./kg./p.o 45

From the results shown in Tables II to VII, and in the following Table VIII, the difierence between the pharmacologically active and the lethal dose is suificiently great to permit the use of the compounds of Formula I in therapeutics.

The compounds of Formula I are useful in the treatment of hypertensions, circulatory troubles, pains due to inflammation, and visceral spasms, and edema.

They may be administered by oral means in the form of tablets, drages or gelules containing 50 to 350 mg. of active ingredient (1 to 3 times a day), by rectal means in the form of suppositories, containing 50 to 350 mg. of active ingredient (1 to 2 times a day) and by parenteral means in the form of capsules containing 5 to 250 mg. of active ingredient (-1 to 3 injections a day).

Accordingly, the present invention also comprises a pharmaceutical composition comprising a compound of the general Formula I together with a pharmaceuticallyacceptable carrier.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound of the formula:

- N-oH,-orr=oH in which R is an alkyl or hydroxyalkyl radical having 1 to 3 carbon atoms; or a radical of the formula:

-CHa -N 1 I in which the N I group represents a dialkylamino radical in which the alkyl has from 1 to 4 carbon atoms, in which the two alkyl radicals are identical, or a heterocyclic radical selected from piperidino, morpholino and pyrrolidino, and the pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1, in which R is methyl.

3. A compound according to claim 1, in which R is 3- hydroxypropyl.

4. A compound according to claim 1, in which R is CH(OH)CH 5. A compound according to claim 1, in which R is CH OH.

6. A compound according to claim 1, in which R is -CH N(nC H 7. A compound according to claim 1, in which R is 8. A compound according to claim 1, in which R is 8 9. A compound according to claim 1, in which R is References Cited UNITED STATES PATENTS 3,080,282 3/1963 Shunk 260-3092 X JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R. 

